A Brief History of MDRS and Nasal Sprays: Advancing Bioequivalence Assessment

In the pharmaceutical industry, the rapid development and approval of generic products, particularly complex generics like nasal sprays, is critical. Traditionally, this process required costly clinical endpoint studies to demonstrate bioequivalence. However, over the past decade, regulators have increasingly accepted alternative methods, including advanced analytical technologies, to streamline this process.

FDA Guidance on Nasal Spray Bioequivalence

The FDA issued draft guidance in 2003 outlining the required tests for assessing the bioavailability and bioequivalence of nasal sprays. These tests include:

• Single actuation content
• Droplet size distribution by laser diffraction
• Drug particle size distribution by microscopy
• Spray pattern and plume geometry
• Priming and repriming
• Drug in small particles/droplets by cascade impactor

Initially, distinguishing between the active drug particles and excipient particles was not possible using available technology, which presented challenges for bioequivalence studies.

Introduction of MDRS

Since then, Morphologically-Directed Raman Spectroscopy (MDRS) has been developed as a more effective tool for assessing nasal spray formulations. MDRS combines particle size and shape analysis with chemical identification through Raman spectroscopy, providing specific data on the size and shape of drug particles. This enables precise bioequivalence assessments without the need for clinical endpoint studies.

In 2014, the FDA accepted MDRS data for bioequivalence evaluation of the first generic mometasone furoate nasal spray, marking a significant shift in how nasal spray generics are evaluated. The FDA highlighted the advantages of using in vitro methods over traditional clinical studies, stating:

FDA accepted the in vitro particle size data from MDRS in lieu of the clinical endpoint BE study… This is a first in OGD history.

MDRS has now been incorporated into many product-specific guidance documents, such as those for Fluticasone Propionate nasal spray (revised in 2019), reflecting its growing acceptance by regulators.

We elaborated on this topic during our webinar Particle profiling and Raman chemical imaging for optimized product formulation, you can also find a summary of the webinar here.

Expanded Use and FDA Resources

As MDRS became more widely adopted, the FDA published additional resources to support its use in bioequivalence studies. In 2019, the FDA published a paper in The AAPS Journal, which explained the approval process for mometasone furoate nasal suspension spray and emphasized the importance of optimizing and validating MDRS methods.

Further updates in 2023 expanded the guidance to include more nasal spray products, offering detailed instructions for sample preparation, particle count determination, and method validation. These resources help pharmaceutical companies navigate the regulatory process more efficiently.

Current Guidance and Best Practices

Today, MDRS is a widely accepted method for evaluating nasal spray bioequivalence. The FDA now provides bioequivalence summary tables that outline the requirements for sample preparation, image acquisition, morphological analysis, and validation. These guidelines enable pharmaceutical companies to submit accurate and well-supported data for regulatory review.

While MDRS has streamlined the approval process, there are still common deficiencies in submissions, such as inadequate detail on sample preparation or image analysis settings. Addressing these issues is crucial for successful approval.

Conclusion

MDRS has significantly advanced the assessment of nasal spray formulations, allowing for faster and more cost-effective bioequivalence evaluations. By following the updated FDA guidance and using MDRS methods, pharmaceutical companies can ensure regulatory compliance and expedite the development of generic nasal sprays.

Curious? Get more information about Morphologi 4-ID, and MDRS. Check our Free webinar on Particle profiling and Raman chemical imaging for optimized product formulation.